Pyrazolopyrimidinones are very well reported for their PDE5 (Phosphodiesterase) inhibitory activity. The well known drug used for erectile dysfunction is ‘Sildenafil’, it contains 5-(2-ethoxyphenyl)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-7(6H)-one as an active ingredient in Viagra.
Phosphodiesterase is an ubiquitous enzyme which selectively catalyzes the hydrolysis of the 3′-cyclic phosphate bonds of adenosine and/or guanosine 3′,5′-cyclicmonophosphate into their respective 5′-nucleosidemonophosphates. cAMP (3′,5′-cyclic adenosine monophosphate) and cGMP (3′,5′-cyclic guanosine monophosphate) are second messengers within cells. These signaling molecules can be generated in two ways. They can carry signals generated by extra-cellular signaling molecules that are incapable of entering the cells. These extracellular signaling molecules, such as hormones or neurotransmitters, bind to membrane bound proteins that in turn activate the particulate forms of adenylate or guanylate cyclase. This activation results in the generation of cAMP or cGMP from adenosine triphosphate (ATP) and guanosine triphosphate (GTP), respectively. Soluble (cytosolic) forms of adenylate and guanylate cyclase also exist and can be activated by messengers within the cell. Soluble adenylate cyclase is activated by calcium signaling to generate cAMP, and soluble guanylate cyclase is activated by nitric oxide (NO) which in turn generates cGMP. The generation and resulting regulation of this signaling are important to many functions throughout the cell. Temporal and spatial regulation of cAMP and cGMP falls to the phosphodiesterases. This is done through the hydrolysis of cAMP and cGMP into their non signaling forms AMP and GMP, respectively (Chappie T. A., Helal C. J., Hou X. J. Med. Chem. 2012, 55, 7299-7331).
There are 11 different PDE families, with each family typically having several different isoforms and splice variants. These unique PDEs differ in their three-dimensional structure, kinetic properties, modes of regulation, intracellular localization, cellular expression, and inhibitor sensitivities. Current data suggest that individual isozymes modulate distinct regulatory pathways in the cell. These properties therefore offer the opportunity for selectively targeting specific PDEs for treatment of specific disease states. (Soderling S. H., Beavo J. A.; Curr. Opin. Cell. Biol. 2000, 12, 174-179; Cote R. H.; Int. J. Impotence. Res. 2004, 16 (Suppl. 1), S28-S33; Bender A. T., Beavo J A.; Pharmacol. Rev. 2006, 58, 488-520.)
Several recently developed compounds are more potent and selective in inhibiting particular PDEs namely PDE-1 (Vinpocetine), PDE-2 (EHNA (erythro-9-(2-hydroxy-3-nonyl)adenine), PDE-3 (Amrinone, Anagrelide, Cilostazol), PDE-4 (Piclamilast, Tibenelast, Benafentrine and Zardaverine) and PDE-5 (Sildenafil, Tadalafin, Vardenafil and Avanafil).
PDE5 inhibitors: Phosphodiesterase (V) inhibitors (PDE5 inhibitors) are an important class of pharmaceutical compounds. The first clinical use of these compounds was in the treatment of male erectile dysfunction (MED), (Boolell M., et al.; Int. J. Impot. Res. 1996, 8, 47-52). Further uses are being proposed and investigated, including pulmonary hypertension (Wilkens H., et al.; Circulation 2001, 104, 1218-1222). There are currently four commercial PDE5 inhibitors which have been approved by the FDA, and these are shown below.

Commercial PDE-5 Inhibitors
The utility of sildenafil as an efficacious, orally active agent for the treatment of male erectile dysfunction (MED), (Terrett N. K., Bell A. S., Brown D., Ellis P.; Bioorg. Med. Chem. Lett. 1996, 6, 1819-1824) has created significant interest in the discovery of additional phosphodiesterase type 5 (PDE5) inhibitors. (Eardley, I. Exp. Opin. Invest. Drugs. 1997, 6, 1803-1810). PDE5 is the primary cGMP-hydrolyzing enzyme present in the corpus cavernosum, the smooth muscle in the penis which helps control vascular tone. When a man is sexually stimulated, nitric oxide is released from the cavernosal nerve. This activates soluble guanylyl cyclase in the corpus cavernosum, causing an increase in intracellular cGMP, which is normally hydrolyzed by PDE5. Inhibition of PDE5 elevates levels of the cyclic nucleotide, leading to enhanced relaxation of smooth muscle, increased arterial inflow, venous congestion, and ultimately an erection. Despite the efficacy of this molecule as a treatment for MED, there are notable drawbacks associated with its use. Clinically significant adverse effects such as nausea, headache, cutaneous flushing, and visual disturbances have been noted and their incidence is dose-dependent. Certain of these are thought to be due to nonspecific inhibition of other PDEs, specifically PDE1 and PDE6. (Beavo, J. A. Physiol. Rev. 1995, 75, 725-748). Thus, the identification of potent and more selective PDE5 inhibitors is of primary interest. We evolved a program for design, synthesis and its evaluation as isoform selective PDE inhibitor.